We have investigated whether a possible dysregulation of the storage and function of islet amyloid polypeptide (IAPP) in the endocrine pancreas of 4-month-old spontaneously diabetic Goto-Kakizaki (GK) rats might contribute to the impairment of glucose-induced insulin secretion previously reported in these rats. Immunocytochemical studies indicated a significantly lower degree of labeling per beta-cell granule of insulin but not of IAPP in GK islets compared to control islets. Further, the GK rats displayed lower plasma levels of both insulin and IAPP in the fasting state. The pancreatic concentrations of both IAPP and insulin were also significantly lower in the GK rats than in the controls. Following an intraperitoneal glucose injection, the plasma IAPP and insulin concentration of the GK rats did not increase at all, whereas a significant increase in both IAPP and insulin concentration was recorded in the control animals. However, the plasma IAPP/insulin ratio was significantly higher in the GK rats at both 30 and 60 min after glucose injection, which may be a reflection of an increased negative feedback effect of IAPP on insulin release. A relative hypersecretion of IAPP might be one of several factors contributing to the impairment of glucose-induced insulin secretion in this rat model of non-insulin-dependent diabetes mellitus. This is further supported by our electron microscopic observations showing disproportionate IAPP/insulin labeling of beta-cell granules in the GK islets.